X-ray contrast composition



Patented Dec. 7, 1943 ,asaz

, 2,336,022 x-nar CONTRAST comosrrron Harden. Leflt and John A. MacLean,New York, N. Y.

No Drawing. Application August 20, 1941, Serial No. 407,684

Claims.

This invention relates to contrast materials adapted to be used in X-rayphotography.

The principal object of the present invention has been to provide afluid substance which is opaque to X-rays and non-toxic to the humansystem. The material is adapted to be used by injecting it into bodycavities wherein the openings which it fills are delineated as shadowareas upon an X-ray photographic negative by virtue of its radioopacity.

Compositions of this type, used by injection, as distinguished frommaterials intended to be ingested orally for examinations of thestomach, have been proposed'and used to a limited extent in the past buttheir use has been unsatisfactory for one or more of several reasons;either they are toxic and cause reactions in the patient, the severityof which varies according to the quantity administered or the cavity inwhich they are disposed, or, on the other hand, the substances are notabsorbed by the system but remain for prolonged periods, sometimescollecting in pockets where their presence causes irritation.

The present invention is directed to a material, which is non-toxie tothe system, 01 such a nature that it is readily absorbed by the body andof sufficient X-ray opacity that injections of it provide the contrastwhich is requisite for good X-ray diagnosis.

Briefly, the contrast compositions of the present invention ar comprisedessentially of diiodo tyrosine. This substance is indigenous to thehuman system being found in relatively small quantitles in excretionsfrom the thyroid gland. We have found that this substance may beinjected into the system in appreciable quantities without subjectingthe patient to toxic reaction or to irritation.

Diiodo tyrosine has the general formula- IC=CH /NH2 HO O CHLCH IC-CII COOH and, upon the molecular basis contains approximately 58% iodine. Byreason of the substantial quantity of iodine which it contains only asmall quantity of diiodo tyrosine is required to endow a substantialvolume of any X-ray transparent fluid with the opacity that is requisitein X-ray photography.

The limited solubility of diiodo tyrosine in water makes administrationsof aqueous solutions of it relatively difiicult since some of thematerial sepally being insufficient to provide the desired contrast.Good definition is obtained by the use of compositions containingapproximately 25% of diiodo tyrosine.

A quantity of colloid is employed in the vehicle in amount suflicient tosuspend the quantity of diiodo tyrosine which is used. Thus, generallyspeaking, the amount of diiodo tyrosine is governed by the opacitydesired and a, sufflcient quantity of colloid is employed to maintainthat amount of diiodo tyrosine in suspension in the vehicle.

Gelatin is the preferred colloid used in the vehicles of the presentinvention because it is nontoxic to the average human system, beingconverted by the body and consumed. -Uponinjection the diiodo tyrosinecomponent is excreted through the kidneys. Absorption takes placerapidly and it is, therefore, to be observed that the X-ray photographyshould be completed within a few hours at the most after injection.

From the clinical point or view, the present contrast compositions maybe used in a variety of ways; for example, by injection with a syringeinto the subarachnoid system of the spinal cord and brain, the lungs,kidneys, anal fistulae, pilonydal cysts, persistent draining sinuses,joint cavities and glands, that is, parotic and submaxillary. Injectionsmay be made, as by catheretization, into the bladder and uterus. Thecompositions, by virtue of their non-toxicity, are adapted particularlyto be used in neuro diagnoses by injection into the ventricles of thebrain, the patient usually suffering no reactions except slightheadaches in some cases or a slight temporary rise in temperature. Inthis latter technique the details of the ventricular system aresuillclently clear as to make fewer views necessary than the twelve totwenty-four X-ray plates heretofore required in the conventional airinjection technique.

The material also has been found useful for injection into the kneejoint in arthritic cases for visualization of the changes in the innersurface of the Joint. In genitourinary examinations mechanical injectioncan be made in the usual way.

For the preparation of a typical composition of the present invention,it has been found satisfactory to prepare a gelatinous vehicle and thensuspend the diiodo tyrosine in it by agitation. A

suitable method for preparing a sterile gelatin vehicle is as follows:

Example To a solution containing approximately 130 c. c. of distilledwater is added 1.8 grams of sodium chloride, 1.0 gram chloro butanol, .2gram of sodium bisulfite, and 40 grams of gelatin (Eastman photographicis suitable). The gelatin is added last and the preparation is mixedvigorously by rotation. This quantity of gelatin is conveniently made ina one liter flask since the mixture tends to boil over if it issterilized in Diiodo tyrosine is added to this gelatin mixture in amountsufiicient to make up a solution of the desired strength, for example, a25% solution; the greater the percentage of the diiodo tyrosine thegreater the opacity of the composition to X-rays. Upon addition of thediiodo tyrosine the preparation is mixed vigorously and aerobic andanaerobic cultures are made and kept to ascertain that the material isbacteriolologically sterile. The composition remains stable forprolonged periods of time if kept in a refrigerator or placed insuitable ampoules. Sterility cultures are made after bottling thepreparation to make sure that'it is suitable for use.

The typical contrast composition made with gelatin is a gel at roomtemperature or at the temperature of the refrigerator in which it shouldbe stored. At body temperature, it is a liquid and, for administration,it can be liquefied most easily, when withdrawn from the refrigerator,by placing the vial in which it is contained in a vessel and covering itfor a few moments with hot water. It is also desirable that the syringebe kept warm while the gel is liquefied to avoid clogging of the needlepassage. Needles of 18 gaugeor larger are suitable for administration ofthe composition by injection.

For use in the subarachnoid the pH of the composition should be betweenthe range of 7.2 to 7.6 and preferably 7.4. For use in other bodycavities it is desirable that the pH of the composition be neutral orsubstantially so.

It has been found preferable to use iodine for halogenation of tyrosine,the amino acid. However, bromine also is opaque to X-rays and dibromotyrosine may be used in place of the iodo compound.

While gelatin is disclosed herein as the preferred colloidal substancein which the diiodo tyrosine may be suspended because it is readilyabsorbed by the body and sufflciently'stable to withstand sterilizing byautoclaving, acacia, arable, and tragacanth and other colloidalsubstances which the body can absorb may be used instead, though itshould be noted that special sterility precautions are required withthose colloids that break down at elevated temperature.

The chemical diiodo tyrosine is commercially available in pure form,however, the supply is limited at present. The product can be made byiodination of the amino acid by one of several different methods, as forexample, the method of E. Abderhalden, reported in Pfleugers Archives,volume 201, 1923, pages 432 to 444.

A typical procedure is to mix 1.8 grams of tyrosine and 4.2 grams ofsodium bicarbonate in 200 c. c. of water. This composition is treated inice, with stirring, with 20 c. c. of N. I. and after two hours, withanother 20 c. c. of 1., whereupon the product is stirred forapproximately three hours. It is believed that mono-iodo tyrosine occursin the formation of diiodo tyrosine but the mono iodide breaks down freehydrogen which combines with another mono-iodo tyrosine molecule formingdiiodo tyrosine.

Having described our invention, we claim:

1. An X-ray contrast composition which is adapted to be used byinjecting it into body cavities, said composition comprising a materialseiii lected from the class consisting of diiodo tyrosine and dibromotyrosine suspended in an aqueous colloidal vehicle.

2. An X-ray contrast composition which is adapted to be used byinjecting it into body cavities, said composition comprising asuspension of diiodo tyrosine in an aqueous vehicle containing gelatin,the said composition being substantially neutral and having a pH valuenot substantially greater than 7.4.

3. An X-ray contrast composition which is adapted to be used byinjecting it into body cavities, said composition comprisingapproximately 10 to 25% by weight of diiodo tyrosine suspended in anaqueous vehicle containing gelatin, the amount of gelatin present in thevehicle being suflicient to maintain the diiodo tyrosine in stablesuspension.

4. An X-ray contrast composition which is adapted to be used byinjecting it into body cavities, said composition comprising an aqueouscolloidal medium having diiodo tyrosine dispersed in it as'the principalcontrast producing agent.

5. An X-ray contrast composition which is adapted to be used byinjecting it into body cavities, said composition comprising asuspension of a material selected from the class consisting of diiodotyrosine and dibromo tyrosine in an aqueous vehicle containing gelatin.

' HAROLD H. LEF'FT.

JOHN A. MACLEAN.

